This invention relates to new 7xcex1, 17xcex1, 17xcex2-substituted testosterone derivatives of general formula I and their use as pure antiandrogens for long-term therapy for androgen-dependent diseases, especially for long-term antiandrogen therapy for prostate cancer.
Current therapies of androgen-dependent diseases are based on the reduction or as complete as possible elimination of androgen-induced effects. This can be done by blocking the domains of androgen receptor (AR), to which the androgens bind as ligands, or by reduction of the available amount of androgens themselves (ligand depletion). In prostate cancer treatment, xe2x80x9cligand depletions meanxe2x80x9d a reduction of the serum testosterone level of testicular origin, which is to be achieved either with use of orchidectomy (removal of a testicle) or by hormone treatment with LRRH analogs or estrogens in high doses. This therapy for inhibiting androgen synthesis and/or reducing androgen concentration is effective only to a limited extent, however, since it has been noted in the meantime that even in the case of total absence of an androgen, non-blocked androgen receptors can be biologically active (ligand-independent AR activation).
As an alternative or as an amendment to xe2x80x9cligand depletion,xe2x80x9d the antiandrogen therapy is used, which is based on the antagonistic blocking of the androgen receptor by so-called xe2x80x9cantiandrogensxe2x80x9d (nonsteroidal or steroidal compounds). Known antiandrogens, which are already used in clinical practice for prostate cancer treatment, are CPA (Schering AG), flutamide (Schering Plough), Casodex (Zeneca) and Anandron(R) (Roussel).
Although 80% of patients first respond to the above-mentioned therapies, almost all of these patients suffer a relapse as early as after an average treatment period of 12-18 months. It has been shown that even the AR blocking by the currently available antiandrogens is inadequate, since the latter either have insufficient active strength and/or can even activate the androgen receptor, i.e. can act like androgens (partial agonism).
Compounds that can act as inhibitors of androgen synthesis and for as blockers of the androgen receptor are also described in WO91/00732. In this case, these are substituted steroids, which have at least one long side chain in one of positions 6xcex1, 7xcex1, 14xcex1, 15xcex1, 16xcex1, 17xcex1 and 17xcex2. Described as preferred compounds are EM 101, a testosterone that is substituted in 17xcex2-position with hydroxy and in 7xcex1-position with a long-chain alkylamide, and EM 150, a testosterone that is substituted in 17xcex2-position with hydroxy and in 17xcex1-position with a long-chain iodoalkine. These compounds also have the above-described drawbacks.
In summary, it has been determined that there is currently no satisfactory therapy for androgen-dependent diseases, such as, e.g., for prostate cancer, and in particular no long-term therapy is possible. The known antiandrogen compounds do not have the necessary active strength to ensure complete blocking of the androgen receptor activity or to have a partially agonistic action.
The object of this invention was therefore to provide potent antiandrogenic compounds that make possible a long-term therapy for androgen-dependent diseases. In particular, prostate cancer can be treated effectively with these compounds.
The object of this invention is achieved by new 7xcex1-, 17xcex1-, 17xcex2-substituted testosterone derivatives of general formula I 
in which
R6 represents a hydrogen atom, a hydroxy group, a C1-C10 alkoxy group, a C1-C10 alkanoyloxy group or a halogen atom,
R15 and R16 each are a hydrogen atom or together form a bond,
R17a represents a C1-C4 alkyl group, a C2-C4 alkinyl group, or a radical of Formula CnFmHo, whereby n=1, 2, 3 or 4, m greater than 1 and m+o=2n+1,
R17b is a hydroxy group, a C1-C10 alkoxy group or a C1-C10 alkanoyloxy group,
A is an unbranched C1-C13 alkylene group,
B represents an oxygen n atom, a grouping xe2x80x94S(O)pxe2x80x94, whereby p=0, 1 or 2, an iminocarbonyl group xe2x80x94C(O)N(Y)xe2x80x94, an imino group xe2x80x94N(Y)xe2x80x94, a carbonylimino group xe2x80x94N(Y)C(O)xe2x80x94, a sulfonylimino group xe2x80x94N(Y)S(O)2xe2x80x94, whereby Y is a hydrogen atom or a C1-C8 alkyl group, a sulfonyloxy group xe2x80x94OS(O)2xe2x80x94, a dimethylsilyloxy group xe2x80x94Oxe2x80x94Si(CH3)2xe2x80x94 or a carbonylsulfanyl group xe2x80x94SC(O)xe2x80x94, or B represents a bond between A and C or together with C forms a bond between A and D,
C represents a bond between B and D, or together with B forms a bond between A and D or an unbranched, C1-C6 alkylene group, a phenylene group, a substituted phenylene group, a five-ring or six-ring heteroarylene group, a substituted five-ring or six-ring heteroarylene group or a five-ring or six-ring heteroarylene group that is condensed with a phenyl ring, and
D represents a hydrogen atom, a C1-C4 alkyl group, a vinyl group, a C1-C4 alkoxy group, a C1-C4 alkoxycarbonyl group, a bis(C1-C4 alkoxycarbonyl)methyl group, an acetyl(C1-C4 alkoxycarbonyl)methyl group, a cyano group, a carboxy group, an azide group, a hydroxy group, a halogen atom or a radical of formula CnFmHo, whereby n=1, 2, 3 or 4, m greater than 1 and m+o=2n+1.
In a preferred embodiment of the invention, R17a in general formula I means the methyl or ethyl group or the trifluoromethyl or pentafluoroethyl group. Radical R17b preferably represents the hydroxy group, a C1-C5 alkoxy group or a C1-C3 alkanoyl group. Quite especially preferably, R17b means the hydroxy, methoxy, ethoxy or acetyloxy group. For radical R6, a hydrogen atom, the hydroxy group or a halogen atom is preferred. In a quite especially preferred embodiment of the invention, the radical ABCD means 9-hydroxynonyl, 7-(acetylsulfanyl)heptyl or 7-(4-cyanobutoxy)heptyl.
For the purposes of this invention, the alkylene groups that are mentioned for grouping A are the heptane-1,7-diyl, the octane-1,8-diyl, the nonane-1,9-diyl, the decane-1,10-diyl, the undecane-1,11-diyl, the dodecane-1,12-diyl and the tridecane-1,13-diyl group. The equivalent applies for the alkylene groups that are defined as grouping C.
The alkyl groups that are mentioned for substituents Y and D stand both for the unbranched groups, i.e., the methyl, ethyl and propyl group, and the corresponding higher homologues, in so far as they are claimed, and for the branched representatives of the above-mentioned carbon atom numbers, e.g., the 1-methylethyl group, the 1-methylpropyl group, the 2-methylpropyl group, the 1,1-dimethylethyl group, etc. Moreover, alkyl groups are also to be defined as cyclic substituents, depending on the above-mentioned carbon atom number, e.g., the cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclopentylmethyl and cyclohexyl radicals.
Alkoxy groups are radicals that are derived from the above-mentioned alkyl groups and extended by one oxygen atom, thus, e.g., the methoxy, ethoxy, propoxy, 1-methylethoxy, 1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy radicals.
For the purposes of this invention, alkanoyloxy groups are defined as hydroxy groups that are esterified with branched and unbranched carboxylic acids of the above-mentioned numbers of carbon atoms, thus, e.g., the formyloxy, acetyloxy, 1-oxopropoxy, 1-oxobutoxy, and 2-methyl-1-oxopropoxy radical.
The arylene and heteroarylene groups that are indicated for grouping C are linked at a substitutable position with grouping B and substituted at another substitutable position with a radical D. Preferred heteroaromatic compounds are pyrrole, thiophene, imidazole, thiazole, oxazole, triazole, thiadiazole, indole, benzoxazole, benzothiazole, pyridine, and pyrimidine. In addition, the arylene or heteroarylene groups can be substituted with a methyl group or a halogen atom.
If a halogen atom is mentioned as a substituent in one of the radicals, a fluorine, chlorine, bromine or iodine atom is suitable for this purpose. Chlorine and fluorine are preferred.
For the purposes of the invention, the following compounds of general formula I are quite especially preferred:
1. 7xcex1-(9-Chlorononyl)-17xcex1-methyl-3-oxoandrost-4-en-17xcex2-yl-acetate
2. 7xcex1-(9-Chlorononyl)-17xcex2-hydroxy-17xcex1-methylandrost-4-en-3-one
3. 17xcex2-Hydroxy-7xcex1-(9-iodononyl)-17xcex1-methylandrost-4-en-3-one
4. 17xcex2-Hydroxy-7xcex1-(9-hydroxynonyl)-17xcex1-methylandrost-4-en-3-one
5. 7xcex1-(10-Chlorodecyl)-17xcex2-hydroxy-17xcex1-methylandrost-4-en-3-one
6. 17xcex2-Hydroxy-7xcex1-(11-hydroxyundecyl)-17xcex1-methylandrost-4-en-3-one
7. 7xcex1-(11-Bromoundecyl)-17xcex2-hydroxy-17xcex1-methylandrost-4-en-3-one
8. 17xcex2-Hydroxy-17xcex1-methyl-7xcex1-[7-(phenylsulfanyl)heptyl]-androst-4-en-3-one
9. 17xcex2-Hydroxy-17xcex1-methyl-7xcex1-[9-[(4,4,5,5,5-pentafluoro-pentyl)sulfanyl]nonyl]androst-4-en-3-one
10. 17xcex2-Hydroxy-17xcex1-methyl-7xcex1-[9-(phenylsulfanyl)nonyl]-androst-4-en-3-one
11. 7xcex1-[9-[(5-Chloropentyl)sulfanyl]nonyl]-17xcex2-hydroxy-17xcex1-methylandrost-4-en-3-one
12. 17xcex2-Hydroxy-7xcex1-[9-[(5-hydroxypentyl)sulfanyl]nonyl]-17xcex1-methylandrost-4-en-3-one
13. 7xcex1-(9-Azidononyl)-17xcex2-hydroxy-17xcex1-methylandrost-4-en-3-one
14. 7xcex1-[7-(Acetylsulfanyl)heptyl]-17xcex2-hydroxy-17xcex1-methylandrost-4-en-3-one
15. 17xcex2-Hydroxy-17xcex1-methyl-7xcex1-[7-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]heptyl]androst-4-en-3-one
16. N-[7-(17xcex2-Hydroxy-17xcex1-methyl-3-oxoandrost-4-en-7xcex1-yl)heptyl]pentanamide
17. 17xcex2-Hydroxy-17xcex1-methyl-3-oxoandrost-4-en-7xcex1-octane-nitrile
18. 5-[[7-(17xcex2-Hydroxy-17xcex1-methyl-3-oxoandrost-4-en-7xcex1-yl)heptyl]oxy]pentanenitrile
19. 17xcex2-Hydroxy-17xcex1-methyl-7xcex1-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]androst-4-en-3-one
20. N-[9-(17xcex2-Hydroxy-17xcex1-methyl-3-oxoandrost-4-en-7xcex1-yl)nonyl]methanesulfonamide
21. 7xcex1-(9-Chlorononyl)-6xcex2-hydroxy-17xcex1-methyl-3-oxoandrost-4-en-17xcex2-yl-acetate
The production of the compounds according to the invention is carried out analogously to the synthesis methods that are described extensively in sterol and steroid literature. The following books form the basis for steroid synthesis: L. F. Fieser and M. Fieser: Steroids: Reinhold Publishing Corporation, NY 1959; Rood""s Chemistry of Carbon Compounds (editor: S. Coffrey): Elsevier Publishing Company, 1971; and especially the xe2x80x9cDictionary of Steroidsxe2x80x9d (editors: R. A. Hill; D. N. Kirk; H. L. J. Makin and G. M. Murphy): Chapmann and Hall. The latter contains a detailed reference list of the original publications up to 1990.
The compounds of this invention can also be produced according to the following general synthesis diagrams and analogously to the production methods that are indicated in the examples. Preferably used as a starting compound is the 3-oxoandrosta-4,6-dien-17xcex2-yl-acetate, whose production is described by Bowers et al. in J. Amer. Chem. Soc. 81, 5991 (1959).
For the case of the production of compounds with a perfluoroalkyl radical in 17xcex1-position, the chain introduction in 7xcex1-position is carried out according to Sakurai (cf. K. Nickisch, H. Laurent, Tetrahedron Lett. 29, 1533-1536 (1988)) with subsequent introduction of a carbonyl protective group in 3-position and subsequent introduction of the perfluoroalkyl radical in 17xcex1-position according to the following diagram (cf. also Examples 1-43): 
In the production of the compounds according to the invention, which have an alkyl or alkinyl group in 17xcex1-position, the chain introduction in 7xcex1-position can be carried out in a way that is known in the art with Grignard""s reagent according to the subsequent diagram: 
Additional derivatization of the alkylene iodide radical that is obtained in 7xcex1-position is done according to commonly used organic synthesis methods and can be performed analogously to these examples.
It has now been found that the compounds of general formula I according to the invention act as pure antiandrogens and thus completely block the androgen receptor activity. The compounds completely inhibit the androgen-stimulated growth of the human prostate carcinoma cell line LNCaP. The compounds according to the invention are thus suitable for long-term antiandrogen therapy for androgen-dependent diseases, such as, for example, carcinoma of the prostate, common acne, hirsutism, early puberty, sexual deviations, androgenic alopecia, non-malignant prostatic hyperplasia or seborrhea.
The subject of the invention is therefore also the use of the compounds of general formula I according to the invention and the compounds, mentioned as preferred, for long-term antiandrogen therapy for androgen-dependent diseases, especially carcinoma of the prostate.
The compounds according to the invention are administered as pharmaceutical compositions, which contain therapeutically effective amounts of one or more compounds of general formula I and optionally galenical adjuvants and/or vehicles, which allow oral or parenteral administration of the agent. The preparations are administered in doses of 1-2000 mg, preferably 5-1000 mg per administration. The subjects of the invention are therefore also pharmaceutical agents, which contain at least one testosterone derivative of general formula I.
The invention is to be explained in more detail in the embodiments below.